With the increased interest in the potential of RNA interference as a therapeutic strategy, novel strategies for siRNA delivery to target tissues are urgently needed. In addition, for a more accurate assessment of the efficacy of the delivery method, non-invasive approaches for detection and tracking of siRNA bioavailability are essential. We have previously described the development of dual-purpose nanoparticle probes for in vivo transfer of synthetic siRNA to tumors and the simultaneous imaging of its accumulation in target tissues by high resolution magnetic resonance and near-infrared optical imaging techniques. These probes consisted of magnetic nanoparticles, labeled with a near-infrared dye, and covalently linked to siRNA molecules specific for model or therapeutic targets. In addition, these nanoparticles were modified with a membrane translocation peptide for intracellular delivery. We demonstrated the feasibility of tracking the in vivo tumor uptake of these complexes by MRI and NIRF imaging in two separate tumor models and also used proof-of- principle optical imaging to corroborate the efficiency of the silencing process. In this proposal, we plan to take this approach to the next level and develop a tumor-targeted imaging and delivery module with the ultimate goal of mediating a therapeutic effect. In the mentored phase of the award, we plan to establish the synthesis and in vitro functionality of our probe. In the independent phase, we will investigate the potential of our tumor-targeted nanoparticle probe, not only as an imaging tool for the assessment of siRNA delivery to tumors, but also as a therapeutic agent capable of inhibiting tumor growth. We will perform therapeutic studies with our probe, alone and in combination with standard chemotherapy, in an attempt to achieve the most significant anti-tumor effects. These studies represent an early step towards exploring the potential of siRNA for tumor therapy. In addition, our planned studies combine imaging and therapeutic agent delivery in a single nanoparticle module, which is essential for cancer therapeutic-product development and optimization. [unreadable] [unreadable] [unreadable]